Beta 3-adrenergic receptors (B3-AR) are thought to play an important role in regulating energy expenditure and B3-selective agonists are being developed as anti-obesity drugs. A number of unresolved issues persist regarding the potential of this receptor as an anti-obesity target. Knockout mice lacking B3-AR have been generated in the previous grant period. The present application proposed to 1) use mice lacking B3-ARs to assess the role of B3-ARs in regulating energy balance: influence of diet and background genes 2) to assess effects of genetically altered a2-AR/B3AR ratios or the Trp64Arg human B3-AR variant on adrenergic signalling in adipocytes; 3) to determine the molecular basis for selective expression of human B3-ARs in brown adipocytes; 4) to use mice lacking B3-AR to establish the existence of additional atypical B-ARs and to molecularly clone and characterize these novel receptors.